Bispecific antibodies and agents to enhance stem cell homing

• US 8,372,399 B2
• Filed: 08/31/2006
• Issued: 02/12/2013
• Est. Priority Date: 08/31/2006
• Status: Active Grant

• Current Assignee: Cardiac Pacemakers Incorporated (Boston Scientific Corporation)
• Original Assignee: Cardiac Pacemakers Incorporated (Boston Scientific Corporation)
• Inventors: Stolen, Craig
• Primary Examiner(s): Kolker, Daniel E
• Assistant Examiner(s): MACFARLANE, STACEY NEE
• Application Number:
  US11/469,081
• Publication Number:
  US 20080057053A1
• Time in Patent Office: 2,357 Days
• Field of Search: None
• US Class Current: 424/136.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: C07K 16/28 against receptors, cell surface antigens or cell surface determinants
• CPC Class Codes: C07K 2317/31 multispecific

Abstract

A composition having a bispecific antibody which binds a stem cell specific antigen and a tissue, differentiated cell or condition associated antigen and an agent that enhances expression of the tissue, differentiated cell or condition associated antigen, is provided. Also provided are methods of using the bispecific antibodies and/or agents to enhance cell therapy.

Claims

1. A composition, comprising:

a bispecific antibody which binds CD34 on a mammalian stem cell and which binds an antigen on a mammalian endothelial cell, wherein the antigen is VAP-1, P-selectin, E-selectin, ICAM, VCAM or VLA; and

an amount of TNF-α

, IFNγ

, IL-1, or IL-4 selected to enhance expression of the antigen in mammalian endothelial cells relative to corresponding cells in the absence of the TNF-α

, IFNγ

, IL-1, or IL-4.

2. The composition of claim 1 further comprising stem cells expressing CD34.

3. The composition of claim 2 wherein the stem cells are recombinantly altered stem cells.

5. The composition of claim 1 or 4, which comprises TNF-α

or IL-1.

6. The composition of claim 5 wherein the IL-1 is IL-1beta.

4. A composition, comprising:

a bispecific antibody which binds a stem cell specific antigen on a mammalian stem cell selected from CD34, CD133, ABCG2, Sca-1, Stro-1, Nestin, PSA-NCAm, p75 neurotrophin, c-kit, or CD30, and which binds VAP-1; and

an amount of TNF-α

, IFNγ

, IL-1, or IL-4 selected to enhance expression of VAP-1 in mammalian endothelial cells relative to corresponding cells in the absence of the TNF-α

, IFNγ

, IL-1, or IL-4.

7. A method of enhancing localization and retention of stem cells, comprising:

delivering to a mammal in need of cell therapy an effective amount of bispecific antibodies which bind CD34 and which bind VAP-1, P-selectin, E-selectin, ICAM, VCAM or VLA, an amount of TNF-α

, IFNγ

, IL-1, or IL-4 that enhances expression of VAP-1, P-selectin, E-selectin, ICAM, VCAM or VLA in mammalian endothelial cells, and donor mammalian stem cells having CD34.

8. The method of claim 7 wherein the bispecific antibodies are contacted with the donor stem cells prior to delivery.

9. The method of claim 7 wherein the donor stem cells are systemically delivered.

10. The method of claim 7 wherein the donor stem cells are locally delivered.

11. The method of claim 7 wherein the donor stem cells are delivered contemporaneously with the bispecific antibodies.

12. The method of claim 7 wherein the bispecific antibodies are systemically delivered.

13. The method of claim 7 wherein the bispecific antibodies are delivered via a catheter.

14. The method of claim 7 wherein the agent is locally delivered prior to the administration of the bispecific antibodies or the cells.

15. The method of claim 7 wherein the donor stem cells are bone marrow cells (BMCs) or mesenchymal stem cells (MSCs).

16. The method of claim 7 wherein the stem cells are autologous or allogenic stem cells.

17. A method for targeting stem cells to a site of injury or inflammation, comprising:

delivering to a mammal having a site of injury or inflammation an effective amount of bispecific antibodies which bind CD34 on a mammalian stem cell and which bind VAP-1, P-selectin, E-selectin, ICAM, VCAM or VLA on mammalian endothelial cells, an amount of TNF-α

, IFNγ

, IL-1, or IL-4 that enhances expression of VAP-1, P-selectin, E-selectin, ICAM, VCAM or VLA in mammalian endothelial cells, and donor mammalian stem cells having CD34, wherein the TNF-α

, IFNγ

, IL-1, or IL-4 is locally delivered to the site of injury or inflammation.

18. The method of claim 7 or 17 wherein the mammal is a human.

19. The method of claim 7 or 17 wherein the IL-1 is IL-1 beta.